The immune system provides a mechanism to protect the body against infection by foreign entities such as infectious organisms or foreign antigens. Under normal conditions, the immune system is capable of recognising and eliciting an immune response against foreign entities, while largely ignoring host tissue. The ability of the immune system to ignore the host's tissue is known as immune tolerance. Immune tolerance also refers to a state where the immune system is adapted to ignore antigens such as transplanted foreign tissues, infected tissues, allergens and malignant tissues.
Autoimmune disease occurs when T cells recognise and react to “self” molecules, that is, molecules produced by the cells of the host. This occurs when specific self molecules interact with proteins on the surface of T cells such that the T cells recognise the molecule as foreign and consequently elicit an immune response against the self molecule. In tissue transplantation, non-self major histocompatibility antigen present on the foreign tissue contacts the surface of T cells, resulting in T-cell activation against the foreign antigen. This activation ultimately results in allograft or xenograft rejection by the immune system.
Present methods for preventing allograft rejection, or for treating autoimmune disease, typically cause a general immunosuppression that is not specific for a specific antigen or antigens. As a result, the subject is rendered susceptible to infection from pathogenic and opportunistic organisms, and may be at an increased risk of malignancy. The more specific immunosuppressive drugs such as cyclosporin A, steroids, azathioprine, anti-T-cell antibodies, rapamycin, mycophenolate mofetil, desoxyspergualine and FK506, typically have undesirable side-effects, and typically require that the subject be administered the drugs for life or at least extended periods of time, thereby placing the subject at considerable risk of infection, cancer, and/or other conditions due to long term effects of the treatment. It would therefore be advantageous to provide a method of inducing tolerance to a specific antigen in a subject. Such a method could be used to suppress the immune response to “self” molecules in a subject having an autoimmune disease, or to suppress the immune response to transplant tissue by inducing tolerance to antigens present on the transplant tissue.
Disease conditions may also result from, or be exacerbated by, the development of immune tolerance to a specific antigen. For example, diseases such as cancer and chronic infections may result from, or progress because of, the development of immune tolerance to tumour or other antigens present on the malignant or pre-malignant cells or antigens of infectious agents expressed by infected cells. It would therefore also be desirable to provide a method of reducing or breaking tolerance to a specific antigen in a subject suffering from disease resulting from or exacerbated by the development of immune tolerance to a specific antigen.
It would further be desirable to provide a method for assessing whether a subject is capable of becoming tolerant to a specific antigen. For example, treatment of patients with immunosuppressive drugs such as cyclosporin A can in some cases lead to tolerance or partial tolerance to specific antigens such as self molecules or alloantigens. If the onset of tolerance could be detected in a patient on such immunosuppressive drug therapy, or in other circumstances, an assessment could be made as to whether the patient still required high levels of immunosuppressive drugs, or whether they had developed sufficient tolerance to a specific antigen to permit the dose of immunosuppressive drugs to be reduced or eliminated.